Saturday, September 27, 2008

Among the many things I did not know about blogging when I undertook to set up this blog is that there is a particular species of subhuman beast that attempts to avertise some product or service by posting "comments" on blogs like this one. The typical form is: "This is a very interesting post. Your readers may be interested to know that Phallix, a drug that give men huge erections that last for 3 months, is available for only $9.99 at your local pharmacy."

I have this blog set up to send me an e-mail when a reader posts a comment. Somehow these advertisers appear to know how to bypass that notification system. I do have control as blogger to pemanently eliminate any comments that I wish to, and whenever I discover one of these ads, I do so. (Those are the only comments that I have ever eliminated, as we have been very fortunate in not attracting comments that are full of obscenities, for instance.) However it may be some time between when the ad appears and when I come across it (or as happened in this latest case, when another faithful reader pointed it out to me). In the meantime please forgive this defacement of a blog that aims to provide noncommercial and valid information.

Friday, September 19, 2008

The HOOKED blog has been on a bit of a vacation while we Galveston refugees try to sort out our lives after Hurricane Ike (this particular one at least having the luxury of a hotel room and an Internet connection). Since any good news is welcome at such a time, I will pass along word that this blog appears to have been cited as one of the 100 best health policy blogs:

--appears to be a harsh criticism of the biotech company. Freking shows how Genentech is digging in its heels, refusing even to provide the drugs for a major scientific study, and insisting that no matter how the study turns out, its present pricing structure will not be affected (that is, insisting that patients with wet macular degeneration have to pay $2000 per dose for Lucentis, while Avastin does the same thing when used off label at $60 per dose).

Both drugs target a protein that causes blood vessels in the back of the eye to grow, but Lucentis is a much smaller molecule. It was specifically designed _ at great expense _ to penetrate the retina. This is bull. Lucentis was specifically designed--at very low expense--to be the classic "me too" or "evergreening" drug. It is simply the active portion of the Avastin molecule--just like Nexium is nothing but the active stereoisomer of Prilosec. Of course the active portion of the molecule is going to be smaller than the entire molecule. The company then spun that as an advantage for eye use. At least some retinal specialists believe the opposite--that the larger Avastin molecule stays around longer and so is more effective.

If Genentech's propaganda were true, then the head-to-head study comparing the two drugs, now underway by the National Eye Institute (no thanks to Genetech) would be expected to show the superiority of Lucentis. Genentech has shown us how much it is willing to bet on that outcome, by saying that regardless of the results of the trial, it won't change its pricing policies. Translated into plain English, that means that all the evidence now available internally to Genetech scientists shows that Lucentis is no better than Avastin.

[Krysta] Pellegrino [Genentech spokesperson] said Genentech's pricing for Lucentis reflects the cost of developing the drug, which the FDA approved in June 2006. The development program included a clinical trial involving more than 6,000 patients at a cost of more than $45,000 a patient."It took decades and hundreds of millions of dollars to develop the drug," she said.

More bull, just as above. Drugs are priced based on what the market will bear, not on how much the company spent to develop them. Once you have figured out what portion of a complex molecule is biologically most active, it is a scientific slam-dunk to cleave off that piece of molecule and run it through trials. Genentech miscalculated, as our earlier post showed. They thought they could cow the retinal surgery community into meekly forking over their patients' life savings by threatening them with lawsuits if anyone suffered harm from the off-label prescribing of Avastin. (And by simultaneously flooding their offices with smiling reps pushing Lucentis.) The retinal surgeons, bless them, mostly stuck to their guns and continues to prescribe Avastin off label in large quantities.

This article is an object lesson in how hard health and science reporters have to work to cut through the misinformation that well-heeled companies will spin for them.

Monday, September 8, 2008

This entry is courtesy our friends over at the Integrity in Science Watch, http://www.cspinet.org/integrity/. Their Sept. 8 press release features a rundown of sweetheart deals recently concluded between big drug firms and major universities, headlined by a 5-year, $25M deal between Harvard and GlaxoSmithKline giving GSK first rights to any patents generated by Harvard scientists around stem cell research. Equal numbers of GSK and Harvard reps sit on the steering committee to oversee this process. Similar deals listed by Integrity include UC-Santa Barbara, Cal Tech, MIT, U Mass, and Columbia all joining forces with AstraZeneca, and I previously blogged about UNC pretty much selling its school of public health to a commercial CRO (http://brodyhooked.blogspot.com/2008/09/cros-how-independent-really.html).

Perhaps the most intriguing part of the Integrity post is this comment: The drug industry is increasingly turning to campus-based researchers to supplement its own lagging research and development efforts, which have fallen on hard times. The number of new drugs coming out of industry labs and approved by the Food and Drug Administration is at record-low levels.

This analysis tends to confirm a trend that I suggested in HOOKED. It is really interesting that the assembly-line, merger-mania model of industrial research that the industry has favored heavily for the past 15-20 years has been such a bust. The industry thought that they could pretty much crank out useful and safe new molecules on demand if they just used a highly industrial system in which business efficiency and close links between R&D and marketing were the operative principles. Turns out, not so. So now the industry is coming back to the academic investigators, whose "inefficient" habits condemned them under the old regime. (Could it be that being really curious about how things work is actually a pretty good way to generate new scientific knowledge? Or that you really ought to try to understand basic mechanisms before you rush off to develop a new drug?)

This is of course good news for a University president frustrated with dropping NIH research budgets and the loss of tax revenues for higher ed., and who is looking to industry as the sugar daddy du jour. It is bad news for those of us concerned about the integrity of science and the huge conflicts of interest that arise when industry takes over the academic enterprise. The sad point is that there are, generally, pretty good ways to get the research done but also to maintain the integrity and separateness of the academic institution. To negotiate such a contract those on the U. side need a backbone, and a couple of other pieces of anatomical equipment best left unspecified in a family blog. In today's race to the pay window, too few universities seem to have the requisite anatomical parts. Even Harvard.

Friday, September 5, 2008

The September 3 issue of JAMA (subscription required) contains three commentaries on the drug industry, providing updates on medicine's relationships. The most newsworthy of them is probably Marcia Angell's (former editor of the New England Journal) analysis of the "broken system" of industry-sponsored clinical research. Dr. Angell concludes that we can no longer allow what most national academic-medicine organizations and leaders persist in assuming to be the bottom line-- that the drug industry will go on funding the clinical trials by which its own products are tested (and that the academic medical center can continue to rake in the resulting research grants plus whatever extras it can scarf up).

Things were not so bad, she recalls, before the 1980s. Then, the industry gave research grants to university investigators who planned and conducted the studies, had control over all the data, and decided on publication. The investigators, or their institutions, seldom had any financial relations with the industry apart from the research grant. Today, by contrast, investigators and their universities are both heavily in bed with the industry, investigators seldom even see the data in their entirety, and the industry staunchly defends a business model in which all data they pay for is their proprietary possession. Dr. Angell also identifies competition from commercial contract research organizations (CROs) and academic centers aping CROs to get the grants (see latest post on UNC selling its School of Public Health to the largest commercial CRO). The result: the problem of bias in research, with companies routinely suppressing data they do not like or else respinning negative studies to make them sound positive, and investigators meekly going along.

The only meaningful solution, says Dr. Angell, is to take the funding of clinical trials needed to assess new drugs out of industry hands, and create a new NIH institute to fund these trials. She repeats this recommendation from her book, The Truth About the Drug Companies, which I cited in giving the same recommendation in HOOKED. If anything, the accumulated data since her book first appeared in 2004 completely reinforce the need for this drastic step.

Though I agree with the recommendation to disconnect trial funding from individual drug companies, Dr. Angell might have said a bit more about what universities and academic leaders can do while waiting for this reform to happen. She seems to view the cozy financial relationships with industry as simply a given in today's world, though she does have some choice words to say about Stanford and its apparent willingness to look the other way as its chair of psychiatry, Dr. Alan Schatzberg, racked up more financial conflicts of interests per square centimeter than any academic in recent memory. (As Dr. Angell notes, when Stanford more recently announced that it had replaced Dr. Schatzberg as PI on his NIMH study of a drug in which he controlled $6M in stock, it claimed that it did so "to eliminate any misunderstanding"-- rather than because his being PI was an unacceptable conflict of interest and violated NIMH rules.) I would have liked to have heard some suggestions as to what the academic medical center could do today to start to better police this industry gravy train.

The core question is whether a CRO is truly independent because (as its defenders claim) it won't get research grants in the future unless it keeps a good reputation for high quality work, and it works for no single drug company; or is ultimately the creature of the industry because (as its critics claim and as I review in HOOKED) in the end, if you don't give drug firms the results they want to market their product, they'll take their business elsewhere. Lenzer gives many examples, mostly drawn from the world of academic CROs, that at least hint strongly at the existence of a decided pro-industry tilt that could seriously bias the research results. She also gives somewhat clearer evidence of a money-laundering operation--that the med school can form an academic CRO, the CRO can take money from a drug company, med school faculty can conduct the research, and when the study is published, all the publicity states that faculty at the med school discovered such-and-such, with nary a mention of the CRO or the company sponsorship.

What I took to be the major pearls from the paper--in the form of smoking guns, to mix metaphors--were:

One of the relatively few major trials demonstrating that serotonin-type (SSRI) antidepressants work in children and teenagers was the TAPS (Treatment of Adolescent Depression) study. This study was carried out by Duke University's academic CRO. The drug under study was Prozxac, made by Eli Lilly. The CRO does a fair amount of work for Lilly. Officially, the TAPS study was sponsored by the NIH. Lilly presumably simply donated the drug. However, TAPS has a number of design features that suggest a considerable bias in favor of Prozac. The worst was the fact that a couple of the arms of the trial were non-blind, when they just as easily could have been blinded, and the non-blind data accounted for a great deal of the total effect size atributed to Prozac. Lenzer noted another bias-suggestive feature--that the scoring system reported those who did better on the drug but omitted any mention of the number who did worse. She then tried to obtain the raw data, on how many did worse, from both the NIH and the principal investigator at Duke. The NIH refused, saying these data were in the possession of the PI. The PI and Duke refused to disclose those data. For a "publicly funded" study this seems strange behavior indeed.

Quintiles Transnational, based in North Carolina, is the world's largest CRO. Its founder and CEO, Dennis Gillings, recently donated $50 million to UNC's School of Public Health--now named the Gillings School of Global Public Health. UNC's chancellor, in writing to Gillings to thank him for the gift, stated that in return, the School would commit to "alignment of faculty behind focused programs," with the priority to be "new methodologies to speed clinical trials innovation." Now, this is odd. A school of public health as a rule is not in the pharmaceutical clinical trials business. If there is any school at the university that you'd expect would be looking at the importance of non-drug approaches to health problems, the School of Public Health would be it. Lenzer also noted that 8 current or former Quintiles executives now either head school programs or sit on advisory boards. Hmm--sounds like a CRO just bought a school of public health--and that UNC meekly handed it over.

This month's Of-All-the-Nerve Award goes to Steven Ferris, PhD of New York University; Douglas Galasko, MD of UC-San Diego, and Louis Kirby, MD of Provista Life Sciences in Phoenix.

Back in April, JAMA published a paper on ghostwriting, based on revelations from the Vioxx litigation and the resulting disclosure of internal Merck documents (see previous post, http://brodyhooked.blogspot.com/2008/04/jama-to-pharma-and-its-allies-enough.html). As an example of a ghostwritten paper with academic "guest authors," Ross et al. discussed in some depth a paper (Thal et al. 2005) listing these gentlemen as co-authors. The three awardees thereupon wrote an angry Letter to the Editor to JAMA denouncing their inclusion in the article as guest authors.

They insisted that all had had "substantial roles" in designing and carrying out the trial. They then admitted: "The paper was initially drafted by Merck coauthors in August 2003, after discussion of the results had previously taken place with Dr Thal and Dr Ferris in June and July 2003. Drs Thal, Ferris, and Kirby were formally approached about being coauthors on the paper and an associated abstract in September 2003. Each critically reviewed the complete statistical report and contributed to revising the final manuscript."

Having this conceded the major point of the accusation against them--that a Merck ghostwriter had in fact been the real "first author" and that they had seen the paper only after it was sent to them, virtually already completed, by the company--Ferris, Galasko, and Kirby went on to complain: "This unsubstantiated allegation of guest authorship raises questions about flawed methodology in the study by Ross et al. It is poor science to draw broad conclusions about pharmaceutical practices from limited and highly selective information. Moreover, neither the authors nor JAMA contacted the presumed guest authors for comments or clarification regarding this material or the allegation of guest authorship prior to publication. A change in author names does not necessarily mean that those added were not involved: such name changes occur frequently as research manuscripts are revised."

"Unsubstantiated"? Ross et al., in their reply to the Letter, remind the readers that as part of their analysis, they had compared the draft prepared by the Merck ghostwriter with the published article, and found only minor changes in wording and organization--so much for the "contributions" to revising the final manuscript.

It may be of some significance that in order to disclose all of their financial relationships with industry, Ferris et al. required 22 lines of fine print following their Letter.

I guess their theory is that the best defense is a good offense. When caught red-handed passing off a ghostwritten paper as your own work, attack the methodology of the expose.

(Thanks to Roy Poses at the Health Care Renewal blog for guiding my attention to this letter.)